合成路线:The alkylation of 2',4''-di-O-(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxime (I) with allyl bromide (II) by means of potassium tert-butoxide in DMSO/THF,followed first by acidification with acetic acid and then by treatment with NaHSO3/HCO2H,gives 6-O-allylerythromycin A (III),which is acylated with acetic anhydride in acetonitrile,yielding the diacetate (IV).Reaction of (IV) with either carbonyldiimidazole (CDI) and LiH or CDI and sodium hexamethyldisilazane (NaHMDS) in THF affords the 12-O-(imidazolylcarbonyl)erythromycin derivative (V),which is cyclized with NH4OH in acetonitrile / THF,giving the cyclic carbamate (VI).Elimination of the cladinose group of (VI) by treatment with HCl in ethanol/water followed by reaction with N-chlorosuccinimide (NCS) and dimethyl sulfide in dichloromethane provides the ketolide (VII),which is condensed with 3-bromoquinoline (VIII) under Heck coupling conditions,palladium acetate,tris(o-tolyl)phosphine and Et3N in acetonitrile,and finally deprotected with MeOH 60-80%.
参考文献标题:Erythromycin A derivs.
文献作者:Adachi,T.; Sekiguchi,K.; Sota,K.; Asaka,T.; Matsunaga,T.; Morimoto,S.; Watanabe,Y.; Kashimura,M.(Taisho Pharmaceutical Co.,Ltd.)
参考来源:EP 0272110; US 4990602
合成路线:A new synthesis of ABT-773 has been reported: The acylation of erythromycin A 9-oxime (I) with acetic anhydride,TEA and DMAP in THF gives the 2',4'',9-tri-O-acetylerythromycin A 9-oxime (II),which is first condensed with 3-(3-quinolinyl)-2-propen-1-ol tert-butyl carbonate (III) by means of Pd2(dba)3 and dppb in toluene and then treated with NaOH to yield 2',4''-di-O-acetyl-6-O-[3-(3-quinolinyl)-2-propenyl]erythromycin A 9-oxime (IV).Reaction of oxime (IV) with NaHSO3 and HOAc in water/THF affords 4''-O-acetyl-6-O-[3-(3-quinolinyl)-2-propenyl]erythromycin A (V),which is benzoylated with benzoic anhydride and TEA in isopropyl acetate/THF to provide 4''-O-acetyl-2'-O-benzoyl-6-O-[3-(3-quinolinyl)-2-propenyl]ery- thromycin A (VI).The reaction of compound (VI) with carbonyldiimidazole (CDI),sodium hexamethyldisilazide (NaHMDS) and ammonia gas in THF/DMF gives the 11-N,12-O-cyclic carbamate erythromycin A derivative (VII).The intermediate 3-(3-quinolinyl)-2-propen-1-ol tert-butyl carbonate (III) has been obtained by Grignard condensation of quinoline-3-carbaldehyde (X) with vinylmagnesium bromide (XI) in THF to give the secondary alcohol (XII),followed by esterification and simultaneous rearrangement with Boc2O in the same solvent.
合成路线:The treatment of cyclic carbamate (VII) with HCl in ethanol produces the cleavage of the cladinosyl sugar moiety,resulting in the 3-hydroxyerythromycin derivative (VIII),which is oxidized with N-chlorosuccinimide (NCS) in dichloromethane to yield the 3-oxoerythromycin A derivative (IX).Finally,this compound is debenzoylated in refluxing methanol.
参考文献标题:Process for preparing 6-O-substd.erythromycin derivs.
文献作者:Hill,D.R.; Cooper,A.J.; King,S.A.; Hsu,M.C.-P.; Napier,J.J.; McLaughlin,M.A.; Deshpande,M.N.; Plata,D.J.; Peterson,M.J.; Leanna,M.R.; Ku,Y.-Y.; Riley,D.; Wittenberger,S.J.; (Abbott Laboratories Inc.)
参考来源:WO 0078773
合成路线:The alkylation of 2',4''-di-O-(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxime (I) with allyl bromide (II) by means of potassium tert-butoxide in DMSO/THF,followed first by acidification with acetic acid and then by treatment with NaHSO3/HCO2H,gives 6-O-allylerythromycin A (III),which is acylated with acetic anhydride in acetonitrile,yielding the diacetate (IV).Reaction of (IV) with either carbonyldiimidazole (CDI) and LiH or CDI and sodium hexamethyldisilazane (NaHMDS) in THF affords the 12-O-(imidazolylcarbonyl)erythromycin derivative (V),which is cyclized with NH4OH in acetonitrile / THF,giving the cyclic carbamate (VI).Elimination of the cladinose group of (VI) by treatment with HCl in ethanol/water followed by reaction with N-chlorosuccinimide (NCS) and dimethyl sulfide in dichloromethane provides the ketolide (VII),which is condensed with 3-bromoquinoline (VIII) under Heck coupling conditions,palladium acetate,tris(o-tolyl)phosphine and Et3N in acetonitrile,and finally deprotected with MeOH 60-80%.
合成路线:Acidic hydrolysis of the cladinose sugar of 6-O-allylerythromycin A (III) with HCl in ethanol/water yields the 3-hydroxy intermediate (IX),which is first protected at the 2'-OH group with acetic anhydride or benzoyl anhydride to (Xa) or (Xb) and then oxidized with NCS and dimethyl sulfide to the 3-oxoerythromycin derivatives (XIa) or (XIb).The reaction of (XIa) with CDI and LiH or (XIb) first with CDI and NaHMDS,then with DBU and finally with CDI and NaH,provides the 12-O-(1-imidazolylcarbonyl)erythromycin derivatives (XIIa) and (XIIb),which are cyclized with aqueous ammonia to the cyclic carbamates (VII) and (XIIIb).Finally,these compounds are condensed with 3-bromoquinoline (VIII) by means of palladium acetate,tris(o-tolyl)phosphine and Et3N in acetonitrile and deprotected with methanol 60-80%.
参考文献标题:Design,synthesis,and characterization of ABT-773: A novel ketolide highly active against multidrug-resistant pathogens
文献作者:Or,Y.; Clark,R.F.; Ma,Z.
参考来源:39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999,San Francisco) 1999,Abst F2133
合成路线:The alkylation of 2',4''-di-O-(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxime (I) with allyl bromide (II) by means of potassium tert-butoxide in DMSO/THF,followed first by acidification with acetic acid and then by treatment with NaHSO3/HCO2H,gives 6-O-allylerythromycin A (III),which is acylated with acetic anhydride in acetonitrile,yielding the diacetate (IV).Reaction of (IV) with either carbonyldiimidazole (CDI) and LiH or CDI and sodium hexamethyldisilazane (NaHMDS) in THF affords the 12-O-(imidazolylcarbonyl)erythromycin derivative (V),which is cyclized with NH4OH in acetonitrile / THF,giving the cyclic carbamate (VI).Elimination of the cladinose group of (VI) by treatment with HCl in ethanol/water followed by reaction with N-chlorosuccinimide (NCS) and dimethyl sulfide in dichloromethane provides the ketolide (VII),which is condensed with 3-bromoquinoline (VIII) under Heck coupling conditions,palladium acetate,tris(o-tolyl)phosphine and Et3N in acetonitrile,and finally deprotected with MeOH 60-80%.
合成路线:Acidic hydrolysis of the cladinose sugar of 6-O-allylerythromycin A (III) with HCl in ethanol/water yields the 3-hydroxy intermediate (IX),which is first protected at the 2'-OH group with acetic anhydride or benzoyl anhydride to (Xa) or (Xb) and then oxidized with NCS and dimethyl sulfide to the 3-oxoerythromycin derivatives (XIa) or (XIb).The reaction of (XIa) with CDI and LiH or (XIb) first with CDI and NaHMDS,then with DBU and finally with CDI and NaH,provides the 12-O-(1-imidazolylcarbonyl)erythromycin derivatives (XIIa) and (XIIb),which are cyclized with aqueous ammonia to the cyclic carbamates (VII) and (XIIIb).Finally,these compounds are condensed with 3-bromoquinoline (VIII) by means of palladium acetate,tris(o-tolyl)phosphine and Et3N in acetonitrile and deprotected with methanol 60-80%.
参考文献标题:Design,synthesis,and antimicrobial activity of 6-O-substituted ketolides active against resistant respiratory tract pathogens
文献作者:Or,Y.S.; Clark,R.F.; Wang,S.; Chu,D.T.W.; Nilius,A.M.; Flamm,R.K.; Mitten,M.; Ewing,P.; Alder,J.; Ma,Z.
参考来源:J Med Chem 2000,43(6),1045-49
合成路线:The alkylation of 2',4''-di-O-(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxime (I) with allyl bromide (II) by means of potassium tert-butoxide in DMSO/THF,followed first by acidification with acetic acid and then by treatment with NaHSO3/HCO2H,gives 6-O-allylerythromycin A (III),which is acylated with acetic anhydride in acetonitrile,yielding the diacetate (IV).Reaction of (IV) with either carbonyldiimidazole (CDI) and LiH or CDI and sodium hexamethyldisilazane (NaHMDS) in THF affords the 12-O-(imidazolylcarbonyl)erythromycin derivative (V),which is cyclized with NH4OH in acetonitrile / THF,giving the cyclic carbamate (VI).Elimination of the cladinose group of (VI) by treatment with HCl in ethanol/water followed by reaction with N-chlorosuccinimide (NCS) and dimethyl sulfide in dichloromethane provides the ketolide (VII),which is condensed with 3-bromoquinoline (VIII) under Heck coupling conditions,palladium acetate,tris(o-tolyl)phosphine and Et3N in acetonitrile,and finally deprotected with MeOH 60-80%.
合成路线:Acidic hydrolysis of the cladinose sugar of 6-O-allylerythromycin A (III) with HCl in ethanol/water yields the 3-hydroxy intermediate (IX),which is first protected at the 2'-OH group with acetic anhydride or benzoyl anhydride to (Xa) or (Xb) and then oxidized with NCS and dimethyl sulfide to the 3-oxoerythromycin derivatives (XIa) or (XIb).The reaction of (XIa) with CDI and LiH or (XIb) first with CDI and NaHMDS,then with DBU and finally with CDI and NaH,provides the 12-O-(1-imidazolylcarbonyl)erythromycin derivatives (XIIa) and (XIIb),which are cyclized with aqueous ammonia to the cyclic carbamates (VII) and (XIIIb).Finally,these compounds are condensed with 3-bromoquinoline (VIII) by means of palladium acetate,tris(o-tolyl)phosphine and Et3N in acetonitrile and deprotected with methanol 60-80%.
参考文献标题:ABT-773
文献作者:Rabasseda,X.; Sorbera,L.A.; Casta馿r,J.
参考来源:Drugs Fut 2000,25(5),445
合成路线:The alkylation of 2',4''-di-O-(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxime (I) with allyl bromide (II) by means of potassium tert-butoxide in DMSO/THF,followed first by acidification with acetic acid and then by treatment with NaHSO3/HCO2H,gives 6-O-allylerythromycin A (III),which is acylated with acetic anhydride in acetonitrile,yielding the diacetate (IV).Reaction of (IV) with either carbonyldiimidazole (CDI) and LiH or CDI and sodium hexamethyldisilazane (NaHMDS) in THF affords the 12-O-(imidazolylcarbonyl)erythromycin derivative (V),which is cyclized with NH4OH in acetonitrile / THF,giving the cyclic carbamate (VI).Elimination of the cladinose group of (VI) by treatment with HCl in ethanol/water followed by reaction with N-chlorosuccinimide (NCS) and dimethyl sulfide in dichloromethane provides the ketolide (VII),which is condensed with 3-bromoquinoline (VIII) under Heck coupling conditions,palladium acetate,tris(o-tolyl)phosphine and Et3N in acetonitrile,and finally deprotected with MeOH 60-80%.
合成路线:Acidic hydrolysis of the cladinose sugar of 6-O-allylerythromycin A (III) with HCl in ethanol/water yields the 3-hydroxy intermediate (IX),which is first protected at the 2'-OH group with acetic anhydride or benzoyl anhydride to (Xa) or (Xb) and then oxidized with NCS and dimethyl sulfide to the 3-oxoerythromycin derivatives (XIa) or (XIb).The reaction of (XIa) with CDI and LiH or (XIb) first with CDI and NaHMDS,then with DBU and finally with CDI and NaH,provides the 12-O-(1-imidazolylcarbonyl)erythromycin derivatives (XIIa) and (XIIb),which are cyclized with aqueous ammonia to the cyclic carbamates (VII) and (XIIIb).Finally,these compounds are condensed with 3-bromoquinoline (VIII) by means of palladium acetate,tris(o-tolyl)phosphine and Et3N in acetonitrile and deprotected with methanol 60-80%.
参考文献标题:Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens
文献作者:Ma,Z.; Clark,R.F.; Brazzale,A.; Wang,S.; Rupp,M.J.; Li,L.; Griesgraber,G.; Zhang,S.-P.; Yong,H.; Phan,L.T.; Nemoto,P.A.; Chu,D.T.; Plattner,J.J.; Zhang,X.; Zhong,P.; Cao,Z.; Nilius,A.M.; Shortridge,V.D.; Flamm,R.K.; Mitten,M.; et al.
参考来源:J Med Chem 2001,44(24),4137
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